Abnormal expressions of genes are closely related to many human diseases, including malignant diseases, endocrine disturbance, immune system disorders, genetic and nervous system disorders, and neurodegenerative disease. The human genome is existed in the form of chromatin structure which is packaged in place by DNA, histones and non-histone proteins, and the chromatin structure plays an important role in determining whether a specific gene is expressive or not. In general, highly packed chromatin suppress transcription, while active expression occurs in those loosely areas of the chromatin.
Inside the nuclei of eukaryotic cells, a nucleosomal core particle is composed of a fragment of DNA (146 bp) wrapped around a histone octamer and the chromatin was formed by the four histone partners and the DNA wrapped around. Histone modifications play important roles in gene transcriptions, DNA replications and DNA repairs. These modifications include methylation, acetylation, phosphorylation of a histone. Among them, the dynamic acetylation level of a histone is catalytically maintained by a pair of enzymes named histone acetylases and histone deacetylases (HDAC). Recent studies revealed that small organic molecules could regulate the histone acetylation level by competitively inhibiting HDACs and thus may be useful in the treatment of carcinoma diseases, cardiac disorders and parasitic diseases, etc. HDACs are now promising targets for diverse drug discovery.
Several classes of HDAC inhibitors (HDACi) have been reported, including (1) short fatty acid, such as butylic acid and phenylbutylic acid; (2) hydroximates, e.g. suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA); (3) Cyclic Tetrapetides with 2-amino-8-oxo-9,10-epoxy-decanoyl, such as trapoxin and HC-toxon; (4) Cyclic Tetrapetides without 2-amino-8-oxo-9,10-epoxy-decanoyl, e.g. Apicidin and FK228; (5) Benzamides, such as MS-275 (EP 0847992, US 2002/0103192, WO 02/26696, WO 01/70675, WO 01/18171). Among them, SAHA was approved by FDA and launched in 2006 as Vorinostat (Zolinza), for the treatment of Cutaneous T-cell Lymphoma (George S. Mack: Journal of the National Cancer Institute, 2006; 98(20): 1443-1444).
WO 01/38322 discloses a HDAC inhibitor represented by the following formula (A):Cy-L1-Ar—Y1—C(O)—NH—Z  (A)
Wherein,
Cy is selected from a group consisting of cylcloalkyl, aryl, heteroaryl or heterocycloalkyl, each of them may be optionally substituted;
L1 is —(CH2)m—W—, m=0-4;
W is —C(O)NH— or —S(O)2NH—;
Ar is a substituted aryl;
Y1 is a saturated or unsaturated hydrocarbon chain with or without substituents;
Z is selected from phenylamino, pyridinyl, thiadiazoyl, and —O-M, where M is H or a pharmaceutical acceptable cation ion.
WO 02/22577 discloses a HDAC inhibitor represented by the following formula (B):

Wherein,
R1 is selected from a group consisting of H, halogen, and linear C1-C6 alkyl;
R2 is selected from a group consisting of H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl and the like.
R3 and R4 are the same or different, and can be independently from each other selected from a group consisting of H, C1-C6 alkyl, acyl, acylamino; or
R3 and R4, together with the carbon atom to which they all combine, form a C═O, C═S or C═NR8; or
R2, together with the nitrogen to which R2 combines, and R3, together with the carbon to which R3 combines, form a C4-C9 heterocycloalkyl, heteroaryl, fused-ring heteroaryl, non-aryl fused-ring heterocyclyl or mixed aryls and non-aryl fused-ring heterocyclyls;
R5 is a H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, and the like;
n, m, p are the same or different, and can be independently from each other selected from 0-6; when n is 1-6, every carbon atom could be independently and optionally substituted by R3 and/or R4;
X and Y are the same or different and are independently from each other selected from a group consisting of H, halogen, C1-C4 alkyl, NO2, C(O)R1, OR9, SR9, CN and NR10R11;
US20060052599 discloses a HDAC inhibitor represented by the following formula (C):

Wherein,
R1 is a lower alkyl, higher alkyl, lower alkenyl, lower or higher alkynyl, lower cycloalkyl, higher cycloalkyl, lower cyclalkyl-lower alkyl, higher cycloalkyl-lower alkyl, lower cycloalkenyl-lower alkyl, aryl-lower cyclo alkyl, lower alkoxy, acyl, aryl, aryl-lower-alkoxy, lower heteroalkyl, amino, heteroaryl, heterocyclyl, and the like;
R2 is a H or lower alkyl; X is a aryl, heteroaryl, cycloaryl, etc: Y is a aryl or heteroaryl, etc; Z is a lower alkenyl, and the like.
U.S. Pat. No. 7,135,493 discloses another HDAC inhibitor shown by formula (D):

Wherein,
R1 is a N-containing heterocycloalkyl and it may be optionally substituted with one or more substituents;
R2 is a hydroxamate:
R3 is a H or a suitable substituent;
L1 is —(CH2)n—, n: 0-6: each of these residual may be substituted by one or more substituent.
L3 is a lower alkenyl.
However, there is still a need to provide further HDAC inhibitors that would be expected to be more effective, to have minimum side effects and more favourable pharmaceutical profiling.